The purpose of this project is to identify the determinants of type 2 diabetes, obesity, and other chronic diseases in the Pima Indians, and elucidate their natural history. Genetic and environmental risk factors for type 2 diabetes have been studied. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Studies of the genetics of type 2 diabetes and obesity are described in project report # Z01 DK 69028 PECR. Behavioral risk factors contribute to the incidence of type 2 diabetes in this population, as self-reported physical inactivity predicts diabetes. A variety of metabolic variables, such as hyperinsulinemia, hyperlipidemia, and obesity also predict diabetes, but each of these entities appears to supply unique information about diabetes risk. Furthermore measures of body fat distribution do not appear to add substantial information about diabetes risk to that obtained by general measures of obesity (i.e. weight and height). Low serum levels of adiponectin predicted diabetes but other inflammatory cytokines, although modestly correlated with adiponectin, were not predictive of diabetes. This suggests that adiponectin may mediate the relationships between inflammation, adiposity and type 2 diabetes.